The majority of men with prostate cancer are now diagnosed with tumors with a low risk of causespecific mortality. Such men are most frequently treated with radical prostatectomy or external beam radiotherapy (EBRT) and are followed by regular serum PSA evaluations thereafter. Most men with a rising PSA post-definitive therapy present several months or years after diagnostic biopsy (in the case of EBRT) or radical prostatectomy (in the case of surgery). Some will have clinically obvious local recurrence, have clinically detectable metastasis, but many will have no other evidence of recurrent prostate cancer other than a rising or detectable PSA. The PSA "doubling time" has been used by some clinicians to determine which of these men deserve adjuvant hormonal ablation, local radiation therapy, or simple observation. We hypothesize that additional biomarkers will help predict which men with a rising PSA post-definitive therapy would benefit from additional therapy. Since many men present with a rising PSA months or years after receiving their definitive therapy elsewhere, the most important biomarkers will be those that can be performed on a specimen that is contemporaneously and easily available, i.e. serum or plasma. The primary goal of Project 1 is to develop potential serum biomarkers that will assist in the management of patients in this situation. However, predicting the prognosis of men at the time of diagnosis is an important direction of current translational prostate cancer research. The secondary goal of Project 1 is to learn if the alterations in the tissue biomarkers at the time of initial diagnosis are associated with later PSA progression and with further systemic progression. To accomplish these focused goals, Project 1 is designed to carefully utilize the patient population resources of the Mayo Clinic prostate cancer practice and the expertise of Mayo Clinic laboratory and clinical scientists. Specific Aim 1 will discover tissue biomarkers associated with prostate cancer progression in patients with rising PSA following definitive treatment. Using the data from Specific Aim 1, Specific Aim 2 will develop serum biomarkers that similarly predict prostate cancer progression in patients with rising PSA following definitive treatment. To begin to translate these associations into clinical practice, Specific Aim 3 will conduct a phase II clinical trial to determine the effect of temporary androgen deprivation in men with a rising PSA after primary definitive therapy and determine the interaction of response to androgen ablation with serum and tissue biomarker alterations. This project will generate new biomarker panels that will be used in the clinical management of a large and important population of men with prostate cancer.